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药品详细

Busulfan(白消安)

化学结构式图
中文名
白消安
英文名
Busulfan
分子式
C6H14O6S2
化学名
4-(methanesulfonyloxy)butyl methanesulfonate
分子量
Average: 246.302
Monoisotopic: 246.02317956
CAS号
55-98-1
ATC分类
L01A 烷化剂
药物类型
small molecule
阶段
approved
商品名
Busulfex;Citosulfan;Leucosulfan;Mablin;Mielevcin;Mielosan;Mielucin;Milecitan;Mileran;Misulban;Mitosan;Mitostan;Myeleukon;Myeloleukon;Myelosan;Mylecytan;Myleran;Myleran Tablets;
同义名
busulfan;Busulphan;Busulphane;Butanedioldimethanesulfonate;Buzulfan;Sulfabutin;Sulphabutin;Tetramethylene Dimethane Sulfonate;Tetramethylenester Kyseliny Methansulfonove;
基本介绍

Busulfan is a bifunctional alkylating agent, having a selective immunosuppressive effect on bone marrow. It is not a structural analog of the nitrogen mustards. It has been used in the palliative treatment of chronic myeloid leukemia (myeloid leukemia, chronic), but although symptomatic relief is provided, no permanent remission is brought about. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), busulfan is listed as a known carcinogen. [PubChem]

生产厂家
  • Glaxosmithkline
  • Otsuka pharmaceutical co ltd
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA: Platelet-derived serotonin mediates liver regeneration. Science. 2006 Apr 7;312(5770):104-7. Pubmed
  2. Valdez BC, Andersson BS: Interstrand crosslink inducing agents in pretransplant conditioning therapy for hematologic malignancies. Environ Mol Mutagen. 2010 Jul;51(6):659-68. Pubmed
  3. Hall AG, Tilby MJ: Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992 Sep;6(3):163-73. Pubmed
  4. Ciurea SO, Andersson BS: Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009 May;15(5):523-36. Epub 2009 Feb 12. Pubmed
  5. McCune JS, Holmberg LA: Busulfan in hematopoietic stem cell transplant setting. Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):957-69. Pubmed
  6. Krivoy N, Hoffer E, Lurie Y, Bentur Y, Rowe JM: Busulfan use in hematopoietic stem cell transplantation: pharmacology, dose adjustment, safety and efficacy in adults and children. Curr Drug Saf. 2008 Jan;3(1):60-6. Pubmed
  7. Nath CE, Shaw PJ: Busulphan in blood and marrow transplantation: dose, route, frequency and role of therapeutic drug monitoring. Curr Clin Pharmacol. 2007 Jan;2(1):75-91. Pubmed
  8. FDA label
剂型
规格
化合物类型
Type small molecule
Classes
  • Sulfonyls
Substructures
  • Sulfonyls
适应症
Cancer 癌症;
药理
Indication For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases.
Pharmacodynamics Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however.
Mechanism of action Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis.
Absorption Completely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg.
Volume of distribution Not Available
Protein binding 32% bound to plasma proteins and 47% bound to red blood cells.
Metabolism
Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity.
Route of elimination Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function.
Half life 2.6 hours
Clearance
  • 2.52 ml/min/kg [Following an infusion of dose of 0.8 mg/kg every six hours, for a total of 16 doses over four days]
Toxicity Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness.
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
melting point 287 dec °C PhysProp
water solubility 6.9E+004 mg/L Not Available
logP -0.52 HANSCH,C ET AL. (1995)
Predicted Properties
Property Value Source
water solubility 5.16e+00 g/l ALOGPS
logP -0.9 ALOGPS
logP -0.76 ChemAxon
logS -1.7 ALOGPS
physiological charge 0 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 86.74 ChemAxon
rotatable bond count 7 ChemAxon
refractivity 49.57 ChemAxon
polarizability 23.64 ChemAxon
药物相互作用
Drug Interaction
Bendamustine Increases toxicity through pharmacodynamic synergism.
Itraconazole Itraconazole reduced busulfan clearance by up to 25% in patients receiving itraconazole compared to those that did not receive it. Concomitant therapy may lead to toxic plasma levels of busulfan.
Metronidazole Metronidazole increases the effect/toxicity of busulfan
Telithromycin Telithromycin may reduce clearance of Busulfan. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Busulfan if Telithromycin is initiated, discontinued or dose changed.
Thioguanine Busulfan increases the hepatoxicity of Thioguanine during long-term concomitant therapy.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of busulfan by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of busulfan if voriconazole is initiated, discontinued or dose changed.
食物相互作用
  • Drink liberally.
  • Take without regard to meals.

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